Diabetes, Vol 49, Issue 2 209-217, Copyright © 2000 by American Diabetes Association

ARTICLES

Inhibitory effect of IGF-I on type 2 nitric oxide synthase expression in Ins-1 cells and protection against activation-dependent apoptosis: involvement of phosphatidylinositol 3-kinase

A Castrillo, OG Bodelon and L Bosca
Instituto de Bioquimica, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.

Challenge of Ins-1 cells, a rat beta-pancreatic cell line, with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) promoted the expression of type 2 nitric oxide synthase (NOS-2) in a cooperative way. Treatment of Ins-1 cells with IGF-I significantly inhibited the expression of NOS-2, especially at subsaturating concentrations of LPS and IFN-gamma. The inhibitory effect of IGF-I on NOS-2 expression was abrogated when cells were incubated with wortmannin or LY294002, two inhibitors of phosphatidylinositol 3-kinase. Transient expression of the p110 subunit of phosphatidylinositol 3-kinase impaired the LPS and IFN-gamma-dependent NOS-2 promoter activity in cells transfected with a 1-kb fragment corresponding to the 5'-flanking region of the NOS-2 gene. However, expression of a dominant negative form of p85 abolished the inhibitory action of IGF-I on the NOS-2 promoter activity. Analysis of the decreased NOS-2 promoter activity in cells incubated with IGF-I showed a lower nuclear factor KB binding as determined by electrophoretic mobility shift assays. The synthesis of NO, produced after LPS and IFN-gamma challenge, triggered an apoptotic response in these cells. IGF-I reduced apoptosis mainly through the decreased synthesis of NO. However, in activated cells treated with N-[3-(aminomethyl)benzyl]acetamidine, a specific NOS-2 inhibitor, IGF-I completely abolished the NO-independent apoptosis. This protection from apoptosis was dependent on phosphatidylinositol 3-kinase activity. These results suggest an important anti-inflammatory and anti-apoptotic role for IGF-I in beta-pancreatic cells, with both actions depending on the activation of phosphatidylinositol 3-kinase.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. L. Holzman, L. Liu, B. J. Duke, A. E. Kemendy, and D. C. Eaton Transactivation of the IGF-1R by aldosterone Am J Physiol Renal Physiol, April 1, 2007; 292(4): F1219 - F1228. [Abstract] [Full Text] [PDF]

				E. Colon, F. Zaman, M. Axelson, O. Larsson, C. Carlsson-Skwirut, K. V. Svechnikov, and O. Soder Insulin-Like Growth Factor-I Is an Important Antiapoptotic Factor for Rat Leydig Cells during Postnatal Development Endocrinology, January 1, 2007; 148(1): 128 - 139. [Abstract] [Full Text] [PDF]

				A. Casellas, A. Salavert, J. Agudo, E. Ayuso, V. Jimenez, M. Moya, S. Munoz, S. Franckhauser, and F. Bosch Expression of IGF-I in Pancreatic Islets Prevents Lymphocytic Infiltration and Protects Mice From Type 1 Diabetes Diabetes, December 1, 2006; 55(12): 3246 - 3255. [Abstract] [Full Text] [PDF]

				X. Li, H. Chen, and P. N. Epstein Metallothionein and Catalase Sensitize to Diabetes in Nonobese Diabetic Mice: Reactive Oxygen Species May Have a Protective Role in Pancreatic {beta}-Cells Diabetes, June 1, 2006; 55(6): 1592 - 1604. [Abstract] [Full Text] [PDF]

				S. Srinivasan, M. Ohsugi, Z. Liu, S. Fatrai, E. Bernal-Mizrachi, and M. A. Permutt Endoplasmic Reticulum Stress-Induced Apoptosis Is Partly Mediated by Reduced Insulin Signaling Through Phosphatidylinositol 3-Kinase/Akt and Increased Glycogen Synthase Kinase-3{beta} in Mouse Insulinoma Cells Diabetes, April 1, 2005; 54(4): 968 - 975. [Abstract] [Full Text] [PDF]

				M. A Martin, P. Serradas, S. Ramos, E. Fernandez, L. Goya, M. N. Gangnerau, M. Lacorne, A. M. Pascual-Leone, F. Escriva, B. Portha, et al. Protein-Caloric Food Restriction Affects Insulin-Like Growth Factor System in Fetal Wistar Rat Endocrinology, March 1, 2005; 146(3): 1364 - 1371. [Abstract] [Full Text] [PDF]

				E. Conti, C. Carrozza, E. Capoluongo, M. Volpe, F. Crea, C. Zuppi, and F. Andreotti Insulin-Like Growth Factor-1 as a Vascular Protective Factor Circulation, October 12, 2004; 110(15): 2260 - 2265. [Full Text] [PDF]

				W. Chen, K. V. Salojin, Q.-S. Mi, M. Grattan, T. C. Meagher, P. Zucker, and T. L. Delovitch Insulin-Like Growth Factor (IGF)-I/IGF-Binding Protein-3 Complex: Therapeutic Efficacy and Mechanism of Protection against Type 1 Diabetes Endocrinology, February 1, 2004; 145(2): 627 - 638. [Abstract] [Full Text] [PDF]

				P. Jambal, S. Masterson, A. Nesterova, R. Bouchard, B. Bergman, J. C. Hutton, L. M. Boxer, J. E.-B. Reusch, and S. Pugazhenthi Cytokine-mediated Down-regulation of the Transcription Factor cAMP-response Element-binding Protein in Pancreatic {beta}-Cells J. Biol. Chem., June 13, 2003; 278(25): 23055 - 23065. [Abstract] [Full Text] [PDF]

				I. Maestre, J. Jordan, S. Calvo, J. A. Reig, V. Cena, B. Soria, M. Prentki, and E. Roche Mitochondrial Dysfunction Is Involved in Apoptosis Induced by Serum Withdrawal and Fatty Acids in the {beta}-Cell Line Ins-1 Endocrinology, January 1, 2003; 144(1): 335 - 345. [Abstract] [Full Text] [PDF]

				W. Liu, C. Chin-Chance, E.-J. Lee, and W. L. Lowe Jr. Activation of Phosphatidylinositol 3-Kinase Contributes to Insulin-Like Growth Factor I-Mediated Inhibition of Pancreatic {beta}-Cell Death Endocrinology, October 1, 2002; 143(10): 3802 - 3812. [Abstract] [Full Text] [PDF]

				A. E. Karlsen, S. G. Ronn, K. Lindberg, J. Johannesen, E. D. Galsgaard, F. Pociot, J. H. Nielsen, T. Mandrup-Poulsen, J. Nerup, and N. Billestrup Suppressor of cytokine signaling 3 (SOCS-3) protects beta -cells against interleukin-1beta - and interferon-gamma -mediated toxicity PNAS, October 9, 2001; 98(21): 12191 - 12196. [Abstract] [Full Text] [PDF]